Bacterial SOS-independent Superfast Evolution of Multi-Drug Resistance

Abstract

AbstractAntibiotic resistance has been a global threat to public health. Majority of antibiotics kill bacteria by inducing the DNA damage. However, bacteria can repair DNA damage via a series of intrinsic pathways including the SOS response. The master regulator of the SOS response is RecA, which was shown to be involved in an enhanced evolution of resistance to fluoroquinolone. Until very recently, the relationship between the evolution of β-lactam resistance and the SOS response remains undefined. Here, we find a superfast evolution of β-lactam resistance (20-fold MIC) following the deletion of RecA in Escherichia coli and treatment with a single dose of β-lactams in 8 hours. Importantly, once this type of resistance being established, it was stable and heritable. Controversially to previous findings, our results indicate this process is completely orthogonal to the SOS response but dependent on the hindrance of DNA repair. In addition, we observe explosive appearance of drug-specific mutations of the bacterial genome in 8 hours of exposure to ampicillin, such as the acrB mutations which is responsible for multi-drug resistance. Together, these findings demonstrate that hindrance of DNA repair not only generally antagonizes cells fitness, but also provides bacteria with genetic plasticity to adapt to diverse stressful environments and can dramatically accelerates the evolution of antibiotic resistance in DNA repair deficiency cells.ImportanceThe evolution of antibiotic resistance can be induced by long-term exposure to antibiotics. However, we for the first time report a superfast evolution of multi-drug resistance induced by a single treatment with β-lactam in DNA repair deficiency Escherichia coli. More importantly, this type of evolutionary trajectory can cause a more rapid spread of drug-resistant bacteria in the community, because once the resistance being established, it was stable and heritable. In addition, from a clinical perspective, our finding significantly highlights the possibility that the synergistic drug combination between β-lactam and inhibitors targeting DNA repair system especially in the patients with cancer treatment can lead to a superfast evolution of multi-drug resistance.